The long term goals of this program are to elucidate the pathogenesis of the phenotypic abnormalities of Down syndrome (DS) (trisomy 21), with particular emphasis on the relationship between DS and Alzheimer disease, and to assess the role of oxygen free radicals in aging and in neuronal function and survival. Studies of Ts16 brains will be carried out to delineate the mechanisms by which the trisomic state causes dysregulation of neuronal gene expression and affects the structure and survival of basal forebrain cholinergic neurons. The possible role in degenerating Ts16 neurons of neuronal death genes and the regulation of such genes by NGF and other neurotrophins will also be investigated. The effects of various types of exogenous oxidative stress on the function and survival of neurons cultured from Ts16 and CuZn-superoxide dismutase (SOD) transgenic mouse brains, both of which have elevated CuZnSOD activities, will be studied, as will the roles of NMDA receptors and of nitric oxide and NO synthetase in glutamate-mediated injury of Ts16 and SOD-transgenic neurons. The effects of oxygen free radicals on longevity an on age- related neuronal degeneration and behavioral changes will be investigated in strains of transgenic mice with a wide range of CuZnSOD activities.